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Lysostaphin treatment of experimental methicillin-resistant Staphylococcus aureus aortic valve endocarditis
M W Climo1, R L Patron, B P Goldstein
1Department of Internal Medicine, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia, USA. CLIMO.MICHAEL@RICHMOND.VA.GOV
Abstract:
The emergence of clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin has prompted a search for new and novel therapeutic agents active against S. aureus. Lysostaphin, a peptidase produced by Staphylococcus simulans, specifically cleaves the glycine-glycine bonds unique to the interpeptide cross-bridge of the S. aureus cell wall. The effectiveness of various regimens of dosing with intravenous lysostaphin was compared to that of vancomycin in the rabbit model of aortic valve endocarditis caused by a clinical methicillin-resistant S. aureus isolate. All animals were treated for a total of 3 days. The most active regimen, lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial counts of 8.5 log10 CFU/g compared to the counts in the untreated controls. In contrast, vancomycin given twice daily sterilized no vegetations and reduced vegetation bacterial counts by only 4.8 log10 CFU/g. Lysostaphin given once daily was less effective, reducing mean vegetation bacterial counts by only 3.6 log10 CFU/g, but the combination of lysostaphin once daily and vancomycin twice daily reduced the mean vegetation bacterial density by 7.5 log10 CFU/g, a result that was significantly better than that for either regimen alone (P < 0.05). Lysostaphin was well tolerated by the rabbits, with no evidence of immunological reactions following up to 9 weeks of intravenous administration. We conclude that lysostaphin given alone or in combination with vancomycin is more effective in the treatment of experimental methicillin-resistant S. aureus aortic valve endocarditis than vancomycin alone.
Insights
Lysostaphin demonstrates superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) endocarditis in rabbits compared to vancomycin. Combination therapy also showed significant benefits, offering a promising alternative for MRSA infections.
Area of Science:
- Infectious Diseases
- Microbiology
- Pharmacology
Background:
- Rising vancomycin resistance in methicillin-resistant Staphylococcus aureus (MRSA) necessitates novel therapeutic strategies.
- Lysostaphin, a peptidase from Staphylococcus simulans, targets the unique S. aureus cell wall structure.
- Endocarditis caused by MRSA presents a significant clinical challenge requiring effective treatment options.
Purpose of the Study:
- To evaluate the efficacy of intravenous lysostaphin regimens against experimental MRSA aortic valve endocarditis.
- To compare the effectiveness of lysostaphin, vancomycin, and their combination in a rabbit model.
- To assess the safety and tolerability of lysostaphin in long-term intravenous administration.
Main Methods:
- A rabbit model of aortic valve endocarditis was established using a clinical MRSA isolate.
- Animals were treated with various dosing regimens of intravenous lysostaphin and vancomycin for 3 days.
- Vegetation bacterial counts were determined, and treatment outcomes were compared to untreated controls.
Main Results:
- Lysostaphin administered three times daily sterilized vegetations in 10 of 11 rabbits, achieving an 8.5 log10 CFU/g reduction.
- Vancomycin (twice daily) failed to sterilize vegetations and resulted in a mean reduction of only 4.8 log10 CFU/g.
- Combination therapy (lysostaphin once daily + vancomycin twice daily) significantly improved outcomes over monotherapy (P < 0.05).
Conclusions:
- Lysostaphin exhibits greater efficacy than vancomycin in treating experimental MRSA aortic valve endocarditis.
- Combination therapy with lysostaphin and vancomycin offers a synergistic therapeutic advantage.
- Lysostaphin was well-tolerated in rabbits, indicating potential for clinical use in MRSA infections.